Faridpur Med. Coll. J. 2016;11(2):74-80

Review Article

Assessment of Ovarian Reserve in Infertile Patients

P Begum1, DR Shaha2, L Sanjowal3, R Barua4, MK Hassan5

Abstract:

Reduced ovarian reserve is a condition characterized by a reduced competence of the to produce due to advanced age or congenital, medical, surgical and idiopathic causes. Age is considered to be the principal factor in determining the reduction of ovarian reserve, especially in woman over 40 years of age, but it's well known that a premature reduction of ovarian reserve can also occur in young patients. Management of patients with diminished ovarian reserve is challenging for fertility experts and frequently the only option to conceive is represented by assisted reproduction technologies. Here we review the aetiology, presentation and diagnosis of reduced ovarian reserve both in advanced and in young age and we discuss recent advances in the management of of these women.

Key words: Reduced Ovarian Reserve; Diminished Ovarian Reserve; Premature Ovarian Failure.

Introduction:

Reduced ovarian reserve is a condition of reduced women the incidence of POF is quickly increasing3. ability of the ovary to produce due to advanced Analyses performed by the Childhood Cancer Survivor age or congenital, medical, surgical and idiopathic Study show that the 6.3% of women who received cure causes. This condition, also known as Diminished for cancer suffered from acute ovarian failure. In this Ovarian Reserve (DOR) is often used to characterize manuscript we reviewed the aetiology, presentation and women at risk for poor performance with Assisted evaluation of old and young woman with reduced Reproductive Technologies (ART) due to egg factor1. ovarian reserve and we discussed recent advances in The most extreme phenotype of DOR in young age is the management of infertility of these patients. represented by Premature Ovarian Failure (POF), a disorder characterized by , Normal Reproductive Aging: hypoestrogenism and high gonadotropin levels in young patients under 40 years of age. Spontaneous The probable theoretical causes of decline in POF affects the 1% of women under 40 years, 0.1% of reproductive potential in women beginning at the third patients younger than 30 years and 0.01% of patients decade of life may be classified as: under the age of 20 years2. However, with the increasing of cancer cures in children and in young i. Diminished ovarian reserve 1. Dr. Poly Begum, MBBS, FCPS (Obst & Gynae), Assistant a. Quantitative decrease in oocytes Professor, Department of Obstetrics & , Diabetic b. Qualitative changes in oocytes Association Medical College, Faridpur. ii. Diminished uterine receptivity for implantation 2. Prof. Dr. Dipti Rani Shaha, MBBS, FCPS (Obst & Gynae), Professor & Head, Department of Obstetrics & Gynaecology, Diabetic Association Medical College, Faridpur. The diminished ovarian reserve, either by decreased quantity and/or quality of the resting follicle pool, 3. Dr. Lipika Sanjowal, MBBS, DA, MCPS (Anaesthesia), Associate Professor, Department of Anaesthesiology, Diabetic Association might decrease fertility after age 30. There is enough Medical College, Faridpur. evidence for both situations. The primordial follicle th 4. Dr. Ripon Barua, MBBS, M.Phil (Microbiology), Assistant count, which is about 20 million at the 20 week of Professor, Department of Microbiology, Faridpur Medical College, intrauterine life, starts to decrease with the process of Faridpur. apoptosis. The primordial follicles left are about 1 5. Dr. Md. Kamrul Hassan, MBBS, DCH (Pediatrics), Junior million at birth and 300 thousands at puberty. At a Consultant (Pediatrics), Faridpur Medical College Hospital, Faridpur. mean age of 37-38 years only about 25 thousands of Address of correspondence : follicles are present in the . After this age, the Dr. Poly Begum, MBBS, FCPS (Obst & Gynae), Assistant disappearance of the follicles accelerates and the curve Professor, Department of Obstetrics & Gynaecology, Diabetic Association Medical College, Faridpur. Cell: +8801913-486864, follows a biphasic pattern. The time interval between E-mail: [email protected] the beginning of 74 Assessment of Ovarian Reserve in Infertile Patients P Begum et al.

accelerated follicular disappearance and is subtle diminished ovarian reserve. For this reason, it constant at about thirteen years. Menstrual cycles will be reasonable to apply ovarian reserve tests become irregular about 6 years before menopause4. liberally to unexplained infertile couples. There is a time period of about 4 years between age 37 when fertility begins to decline and age 41 when The effect of diminished ovarian reserve on fertility fertility practically ends5. It is known that the age of outcome has largely been evaluated in patients treated menopause in the general populationis under 45 in 10% with ART. In this group of infertile patients the clinical of women and under 40 in 1% of women. Thus, if the entities associated with diminished ovarian reserve are time interval between the beginning of accelerated poor response to COH, increased need for exogenous follicular disappearance and menopause is constant and gonadotropin, high cancellation rates, low about thirteen years it can be speculated that about 10% and live birth rates in ART. On the other hand, data of women in the general population will suffer from the regarding the reproductive outcome of ovulatory clinical consequences of impaired fertility in their women in a general infertility population with an thirties due to early ovarian aging. The data from ART abnormal ovarian test is insufficient. Hence, the cycles with fresh and non-donor oocytes and embryos treatment alternatives to increase the chance to have a demonstrate a decrease in embryo implantation, baby, especially in patients with an abnormal ovarian pregnancy and live birth rates per cycle when female reserve test and younger than 35 years of age, are not partner age exceeds 38. In ICSI cycles of men with yet known. obstructive azoospermia, the implantation rate decreases if the female partner age is over 37; this Ovarian Reserve Tests: finding also demonstrates the effect of age related decline in oocyte quality on reproductive performance6. Basal follicle stimulating hormone (FSH) level: Basal Data obtained from oocyte donation clearly shows that, or cycle day 3 FSH level is an indirect indicator of if oocytes are donated from young women to older ovarian reserve. It reflects the negative feedback effects women, both embryo implantation and pregnancy rates of inhibin-B and produced by a cohort of are restored to normal levels. These results suggest that follicles at pituitary level. Most of the studies of basal the effect of age on fertility is largely a result of FSH levels are from ART cycles. The cut-off values for qualitative changes within the aging oocytes, rather basal FSH vary from 10 to 25 IU/l. The value of basal than senescent changes in the . The high rates of FSH as a test for ovarian reserve in ART was evaluated pregnancy wastage in older women also indicate the in a meta-analysis of 21 studies. The results of receiver age-related decrease in oocyte quality7. Detection of operating curve (ROC) analysis have shown that the high abortion rates in oocyte donation cycles if oocytes performance of basal FSH in ART cycles to predict poor are donated from older women demonstrates that the response was moderate, where as to predict non- age-related factor responsible for pregnancy wastage is pregnancy was poor. In a systemic review, Broekmans also oocyte quality8. An increased frequency of et al10 found that the cut off FSH levels of > 10U/ L had abnormal chromosome arrangements in human oocytes a specificity of 80-90% and a lower sensitivity of 10- in older women is reported in several studies. Pre- 30% for the prediction of poor ovarian response to implantation genetic diagnosis of embryos in women gonadotropin in IVF. The lack of clear cut-off point over 38 shows high rates of aneuploidy, another with reasonable sensitivity and specificity and inter- important evidence of a strong association between cycle variations of FSH measurements also limits the and pregnancy wastage9. reliability and use of basal FSH in IVF practice. The increase in basal FSH levels is a late indicator of Initial Evaluation of Ovarian Reserve: ovarian reserve. Median FSH remained consistently low (>_5 U/L) in women >_ 35 years of age and was 6 U/L in An important group of patients that has to be taken into 35 to 40 years old11. Prediction of over reserve with consideration for diminished ovarian reserve are only basal FSH may lead to an inappropriate strategy in infertile women of advanced age (>35). The proportion infertile women, and some with a diminished ovarian of older age infertile women is gradually increasing. If reserve cannot take advantage of determining the 10% of patients enter menopause before the age of 45, rapidly closing window of opportunity. Although it is then the same proportion of women are expected to known that the prognosis of ART cycles will be highly experience signs of ovarian aging in their early thirties. negative in patients with high basal FSH levels, it is Thus, it should be reasonable to test all infertile women generally accepted that the predictive value of FSH over 30 for ovarian reserve. Ovarian surgeries of any levels below cut-off values are limited to reflect the kind, but particularly for ovarian , might outcome of ART cycles. A study evaluating the be detrimental to primordial follicle pool; thus, patients predictive value of FSH with regard to age showed that with a history of ovarian surgery need to be evaluated the ART performance of the patients over 40 but with for ovarian reserve regardless of their age. The normal basal FSH levels were worse than the patients underlying cause of subfertility might theoretically be a below 40 but with an abnormal basal FSH level. That is 75 Faridpur Medical College Journal Vol. 11, No. 2, July 2016

to say, age reflects oocyte quality whereas basal FSH 6% for basal FSH screening alone. The use of the CCC reflects oocyte number and the outcome of an ART test for screening ovarian reserve in a general infertile cycle will be better if oocytes can be retrieved despite population was assessed only in a large series. About high basal levels in younger patients. A normal basal 10% of infertile women had anabnormal CCC test FSH level does not negate the effects of chronologic result and the fecundity of patients with an abnormal age on oocyte quality, embryo implantation, and test was extremely decreased. pregnancy rates, and expectations should be managed accordingly. There are only a limited number of studies Basal serum Inhibin-B levels: Inhibin-B is a dimeric in which ovarian reserve tests were used to predict peptide that is secreted by granulosa cells of preantral fertility prognosis in a general infertility population12. and early antral follicles13. Therefore it is thought to In one of these studies, the predictive value of elevated have some value as an ovarian test. Inhibin- B basal FSH levels during the initial sub fertility workup concentrations decline before a rise in basal FSH levels with respect to fecundity has been assessed in a general and thus shows the reduction of in ovarian reserve infertility population. Long-term follow up has shown earlier than basal FSH14. As the level of inhibin-B that the pregnancy rates and time interval to pregnancy decreases, ovarian response to, gonadotropin, the were not different between patients with either normal number of oocytes retrieved and pregnancy rates or high basal FSH levels. It was concluded that decrease. Although there is a correlation between basal screening for high basal FSH levels was of no Inhibin-B levels and ovarian response, it has low additional value in a general infertile population. sensitivity (60-90%), specifity (40-80%) and positive predictive value (19-22%) even in low threshold values Basal serum estradiol levels: Early elevations in (40-45pg/mL)15. In various studies investigating the serum estradiol reflect the advanced follicular relationship between basal inhibin-B and ART development and early selection of a dominant follicle outcomes, it was concluded that inhibin-Blevel was not driven by rising FSH levels. A premature estradiol a reliable measure of ovarian reserve and had apoor elevation may suppress the FSH levels, masking predictive value for pregnancy16. elevation that might otherwise reveal a low ovarian reserve. Patients with basal estradiol levels of 80 pg/ml Anti-Mullerian Hormone (AMH): Anti-mullerian or higher during a cycle before IVF achieved a lower hormone is produced by granulosa cells of preantral pregnancy rate per initiated cycle (14.8% versus and small antral follicles. The secretion begins from the 37.0%) and had a higher cancellation rate (18.5% start of primordial follicle growth and continues until versus 0.4%), compared with those with estradiol levels the follicles have become capable of responding to below 80 pg/ml. Even if FSH >15 were excluded, FSH, which occurs when the diameter of the follicle elevated basal estradiol levels still correlated with poor reaches 4-6mm. AMH is not expressed in atretic ovarian response and higher cancellation rates. As an follicles and theca cells. The gonadotropin independent ovarian test basal estradiol level has little value but expression of AMH results of minimal variation within may provide additional data in basal FSH and between cycles provides advantage over other interpretation. Adding cycle day 3 estradiol ovarian reserve markers. Pregnancy, the use of measurement to FSH decreases the incidence of false- gonadotropin agonists for ovarian suppression, the day negative results based on FSH alone. of dose do not affect serum levels. AMH expression is observed as early as the 36' Clomiphene Citrate Challenge Test (CCC Test): The gestational week, serum levels are gradually increased physiological basis of the CCC test is that, in a group of in the first 3-4 years of life and become stable until patients with diminished ovarian reserve but normal puberty. As the number and quality of the oocytes FSH levels, CC induced serum FSH rise cannot be diminish throughout the woman's reproductive life, suppressed by decreased inhibin secretion from a serum concentrations of AMH gradually decrease and fall decreased primordial follicle pool and elevated levels below detectable levels in the menopause. Median time of of FSH are measured after CC administration. The test menopause can be predicted by using AMH levels more is considered abnormal if any measurement of FSH accurately than Inhibin and basal FSH. The number of the either on day 3 or on day 10 after CC administrationis residual follicular pool correlates with the number of small higher than 10 IU/l. The predictive value of an antral follicles and AMH levels17. The first study abnormal CCC test is extremely high with an overall investigating the relation between AMH levels and cumulative pregnancy rate of only 1.3%, which is ovarian response to gonadotropin on ART cycles was comparable with the 1.5% cumulative pregnancy rate performed in 2002. From that time on numerous studies among women with abnormal day 3 FSH values in have been, performed. In women undergoing ART, low ART cycles. Nevertheless, among older, at risk AMH threshold values (0.2-0.7 ng/mL) have 40-97% patients, the CCC test also identified 29% of patients sensitivity, 78-92% specificity , 22-88% positive with compromised fecundity as compared to a rate of predictive value and 97-100% negative

76 Assessment of Ovarian Reserve in Infertile Patients P Begum et al.

predictive value for prediction poor response to the best predictors of the total number of follicles stimulation, but donot predict pregnancy18. Almost all obtained after maximal ovarian hyper stimulation in an studies revealed that there had been a correlation IVF treatment; CCCT, basal FSH and estradiol, age between AMH levels and retrieved oocyte number and show a much lower performance. EFFORT and GAST AMH seems to be a better marker than age, basal FSH, are more complex, expensive and time consuming and estradiol, Inhibin-B in predicting ovarian response to the predictive value in ovarian response or pregnancy gonadotropin but, when compared with AFC, it has are not so different from conventional markers. It is not nearly the same capacity to predict ovarian response19. advised to use these tests routinely in the evaluation of ovarian reserve. In a recent study including 1043 IVF cycles, AMH levels were found to be significantly related with the Assessment of ovarian reserve by Ultrasonography: rate of ongoing pregnancy both in fresh and frozen 20 Comparison of an indirect assessment of ovarian embryo transfer cycles . In a meta-analysis, a total of reserve by sonographic measurement of ovarian 13 studies were analyzed reporting on AMH and 17 on volume and antral follicle counts with other ovarian AFC and it was shown that AMH had at least the same reserve tests in ART cycles and their performance to level of accuracy and clinical value for the prediction predict response to COH and pregnancy rates have of poor response and non-pregnancy as AFC. Both recently been reported in many studies. The most AMH and AFC have limited accuracy for non- important advantage of Ultrasonography is that it can pregnancy prediction21. Besides retrieved oocyte be done in every patient without any additional cost. number, AMH and AFC are also found to be The sonographic assessment of ovarian reserve is also comparable predictors of the number of good quality advantageous in selecting poor responders and embryos available for transfer and freezing22. However, choosing appropriate stimulation protocols at the AMH determination has some advantages overAFC: 1) beginning of the cycle. it does not have to be carried out on a specific day ofthe cycle because of stability in serum levels throughout i. Measurement of ovarian volume: The age-related the menstrual cycle. 2) There is no need for a skilled decline in primordial follicle pool is supposed to cause a decrease in ovarian volume. The decrease in ultrasound operator to count ovarian follicles 3) A ovarian volume is supposed to be more pronounced possible observer bias in ultrasonographer is 23 after the age of 38 till menopause, a time period eliminated. In their study, Silberstein at al found that when the follicular depletion is accelerated. In a the serum AMH levels at the time of hCG study population of women 14 to 45 years of age administration seem to predict not only ovarian reserve, attending a clinic, no correlation has but also embryo morphology. Some studies in the been detected between age and ovarian volume. In a literature have revealed that there is a correlation study with healthy and fertile Chinese women it was between oocyte quality and AMH levels but other found that the ovarian volume was not different studies have defended the opposite. throughout the whole reproductive period. In a similar study population, but in the age group of 35 GnRH stimulation test (GAST): Administration of to 50 years, the mean ovarian volume was detected to GnRH agonists on cycle day 2-3 causes an initial surge be similar in three age groups of 35 to 39, 40 to 44 of FSH, LH and estradiol. The response of estradiol is and 45 to 49 years and the correlation of decrease in ovarian volume was evident only in the age group of an indirect indicator of ovarian reserve. If the follicular 25 cohort is small, GnRH agonists may lead to less 45 to 49 . Interestingly it was found in the same age estradiol increase. In two prospective studies it is groups that ovarian volume was decreased in infertile shown that the response of estradiol to GnRH-a women compared to age-matched fertile women. stimulation was highly correlated with ovarian response Although the ovarian volume was least in unexplained infertile patients, the difference did not in ART cycles. Exogenous FSH ovarian reserve test reach significance. Data on the predictive value of (EFFORT):- In the exogenous FSH reserve test, FSH ovarian volume measurement on IVF cycles has and estradiol, inhibin levels are determined before and demonstrated that although a correlation between 24 hours after administration of 300 IU recombinant response to COH and ovarian volume was present, FSH on day 3 of the menstrual cycle. Basal FSH levels the predictive value of ovarian volume measurement and increase in estradiol levels are used to predict for pregnancy was poor26. High cancellation rates ovarian response in ART cycles. In a prospective study have also been reported in women with ovaries investigating the predictive value of EFORT in 52 IVF measuring less than 3cm. cycles; it was shown that at least 30 pg/mL increases in estradiol levels is a better predictor of ovarian response ii. Antral follicle counts: The age-related decline in than basal FSH. In another prospective randomized the number of antral follicles less than 10mm study performed by Kwee et al24 CCCT and EFORT measured by ultrasound has been shown in several were compared in terms of ovarian response in 110 studies. In a study population of fertile women a biphasic pattern has been demonstrated in age related ART cycle and it was found that the inhibin B 27 increment and estradiol increment in the EFORT are decline in antral follicle counts . A yearly decline of 77 Faridpur Medical College Journal Vol. 11, No. 2, July 2016

4.8% before the age of 37 was accelerated there after A study assessing the accuracy of basal FSH, estradiol, to the rate of 11.7%. However, a monophasic yearly CCCT, GAST in predicting the total number of decline of 3.8% has been demonstrated in a fertile follicles, which was determined by histological population in another study. The correlation of antral examination of oophorectomy materials in 22 fertile follicle counts with poor response in IVF has been patients older than 35 years, found a positive several studies28. In a recent study investigating the correlation between only basal estradiol levels and role of AFC in IVF outcome prediction, it has been follicle per unit but not with others34. The uneven shown that antral follicle count was predictive of distribution of follicles in the ovary makes a large ovarian response, with a 67% likelihood of poor variation even in the same ovary. When the random ovarian response for AFC >_ 4, also there was a follicular distribution and potential risks of procedure significant linear relationship between AFC, age and are taken into consideration together, this procedure is live birth which is much more marked for AFC. A not justified on current available data. study comparing the effectiveness of basal and CC induced inhibin-B and FSH, ovarian volume and Combination of ovarian reserve tests: None of the antral follicle counts to predict the outcome of IVF tests has a 100% sensitivity and specify used for poor cycles, reported that ovarian volume was the best ovarian response prediction. In order to increase the parameter to predict poor ovarian response to COH, prognostic reliability of each test, combining the whereas age and antral follicle counts were found to ovarian tests may be considered. A scoring system be better than the other test with respect to predicting using the combination of age, AFC, basal FSH, basal pregnancy success. In conclusion, it can be suggested AMH, delta E2 and delta inhibin developed by that antral follicle counts reflect the ovarian reserve Muttukrishna et al35 predicted the ovarian response better than ovarian volume in infertile patients. more accurately than each of the parameters alone. However, in a meta-analysis investigating the iii. Ovarian stromal blood flow: There is a positive performance of the combinations of ovarian reserve and independent correlation between ovarian stromal tests to predict ovarian response in IVF, the peak systolic velocity (PSV) measured by combination of these tests did not perform better transvaginal pulsed Doppler Ultrasonography both in compared with AFC alone. According to this meta- the early follicular phase and after pituitary analysis there is no advantage in using multivariate suppression29. Engman et al29 showed that ovarian model in poor response prediction36. Addition of age, stromal PSV was the most important single AFC, basal FSH, Inhibin to AMH did not make a independent predictor of ovarian response in patients significant difference in prognostic reliability of AMH with a normal basal serum FSH level, compared to in a recent study37. The high level correlation of age, FSH/LH ratio, estradiol levels if the cut-off level ovarian reserve tests and the differences of chosen for PSV was taken as 10cm/s. A study using 3D thresholds for each test make analysis difficult. ultrasound reported that ovarian stromal vascularity Although ovarian reserve tests reflect oocyte quantity was associated with a higher number of retrieved they do not reflect oocyte quality accurately38. Age was oocytes and increased pregnancy rates30. Contrary to found better in predicting pregnancy than these tests38. this Jarvela et al31 reported quantification of power Women with low ovarian reserve still have a Doppler signal in the ovaries after pituitary reasonable chance to achieve pregnancy. The increased suppression does not provide any additional rates of spontaneous abortus and aneuploidy in young information to predict the subsequent response to women with poor ovarian reserve suggest that oocyte gonadotropin stimulation during IVF. In a recent quality may also contribute in some unexplained study, early follicular stromal Doppler signals are infertile women. Counseling and management of the correlated with ovarian response and basal ovarian cycle with the knowledge gained only from the ovarian reserve parameters, but has no correlation with age or reserve tests is a matter of debate. In fact, many women with clinical pregnancy achievement in infertile whose tests results were lower than the cut-off could women undergoing IVF-ET treatment32. Further have pregnancy after IVF. studies are needed to clarify the effect of ovarian stromal blood flow on ART outcomes. Conclusion:

Ovarian Biopsy: Demonstration of primordial follicles Assessment of ovarian reserve should not be neglected depletion in the ovary by ovarian biopsy was studied in an infertile patient if the age of the patient is above by several authors. Lass et al.33 in their investigation the period when the ovarian reserve is known to be attempted to find if there had been correlation between declining. At present, there is no ideal ovarian reserve basal estradiol levels, ovarian size and follicular test reflecting fertility potential of a woman reliably. density in 60 infertile women. Computerized image Controversial results of the studies make it difficult to analysis was used to measure the number of follicles compare the efficiency of different tests of ovarian per unit volume of ovarian tissue. There was no reserve. Data obtained from ART cycles are useful to significant difference between unexplained and tubal form models for assessing the efficiency of various infertility patients. They also observed that follicular tests to predict fertility potential. None of the tests of density diminished significantly with increasing age. ovarian reserve is ideal to predict pregnancy. A woman

78 Assessment of Ovarian Reserve in Infertile Patients P Begum et al.

with an abnormal ovarian test may conceive either 12. van Montfrans JM, Hoek A, van Hooff MHA, de Koning CH, spontaneously or by ART. Although the predictive Tonch N,Lambalk CB. Predictive value of basal follicle stimulating hormone concentrations in a general subfertility value (specificity) of an abnormal hormonal parameter population. Fertil Steril. 2000; 74:97-103. (basal or CC induced FSH and Inhibin) to detect diminished ovarian reserve is high, their sensitivities 13. Rosencrantz MA, Wachs DS, Coffler MS, Malcom PJ, Donohue are low. The CC test is relatively more sensitive than M, Chang RJ. Comparison of inhibin B and estradiol responses to basal FSH. Among the ultrasound parameters, an antral intravenous FSH in women with polycystic ovary syndrome and follicle count is the most reliable. There are only a normal women. Hum Reprod. 2010; 25:198-203. limited number of studies in which ovarian reserve 14. Seifer DB, Scott RT Jr, Bergh PA, Abrogast LK, Friedman CI, tests were used to predict fertility prognosis in a Mack CK, et al. Women with declining ovarian reserve may general infertility population. The most reliable tests in demon stratea decrease in day 3 serum inhibin B before a rise in these patients seem to be AFC and AMH, according to day 3 follicle stimulating hormone. Fertil Steril. 1999; 72:63-5. the existing data. The studies in this group of patients will aid in forming screening strategies for 15. Marc A. Leon. . In: Marc A. Fritz Leon editors. Clinical Gynecologic Endocrinology and Infertility, 8th edition. asymptomatic cases of diminished fertility due to early Philadelphia: USA; 2011. p. 1150-2. ovarian aging in the general population. AMH has advantages compared with other markers of ovarian 16. Smeenk JM, Sweep FC, Zielhuis GA, Kremer JA, Thomas CM, reserve tests. It is the earliest marker to change with Braat DD. Anti-mullerianhor mone predicts ovarian age and has least inter and intra cycle variability. responsiveness, but not embryo quality or pregnancy, after in vitro fertilization or intracytoplasmic sperm injection. Fertil Steril. 2007; 87:223-6. References : 17. van Rooij IA, Tonkelaar I, Broekmans FJ, Looman CW, Scheffer 1. teVelde ER, Pearson PL. The variability of female reproductive GJ, de Jong FH, et al. Anti müllerian hormone is a promising ageing. Hum Reprod Update 2002; 8:141-54. predictor for the occurrence of the menopausal transition. Menopause. 2004;11:601-6. 2. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996; 17:121-55. 18. Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri DM, Serhal P. Antral follicle count, anti-mullerian hormone and 3. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. inhibin B: predictors of ovarian response in assisted reproductive Accelerated disappearance of ovarian follicles in mid-life: technology? Br J Obstet Gynaecol. 2005; 112:1384-90. Implications for forecasting menopause. Hum Reprod. 1992; 7:1342-6. 19. La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio AC, et al. Anti-Mullerian hormone (AMH) as a 4. Treloar AE. Menstrual cyclicity and the premenopause. predictive marker in assisted reproductive technology (ART). Maturitas.1981; 3:49-64. Hum Reprod Update. 2010; 16:113-30. 20. Honnma H, Baba T, Sasaki M, Hashiba Y, Oguri H, Fukunaga T, 5. van Zonneveld P, Scheffer GJ, Broekmans FJ, teVelde ER. et al. Serum Anti-mullerian Hormone Levels Affect the Rate of On Hormones and reproductive aging. Maturitas. 2001; 38:83-94. going Pregnancy After In Vitro Fertilization. Reprod Sci. 2012 Jul 18. 6. Silber Z, Nagy Z, Devroey P, Camus M, Van Steirteghem AC. The 21. Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of anti- effect of female age and ovarian reserve on pregnancy rate in male Mullerian hormone in prediction of outcome after IVF: infertility: treatment of azoospermia with sperm retrieval and comparison with the antral follicle count. Fertil Steril. 2009; intracytoplasmic sperm injection. Hum Reprod. 1997; 12:2693-700. 91:705-14.

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